tbuckley/cabot-search huggingface dataset:
SURG-41. MACHINE LEARNING PREDICTS THE INFLUENCE OF FRAILTY ON THE CLINICAL MANAGEMENT OF NEUROFIBROMATOSIS TYPE 1: A MIXED-EFFECTS MODELING STUDY USING THE NATIONWIDE READMISSIONS DATABASE
Authors: Shane Shahrestani, Nolan Brown, Julian Gendreau, Gabriel Zada
Journal: Neuro-Oncology (2022)

Abstract Recent literature has highlighted the association of frailty with significantly higher rates of morbidity and mortality in patients with CNS neoplasms. However, there is a paucity of research regarding the effects of frailty as it relates to neurocutaneous disorders, namely NF1. In this study we evaluated the role of frailty in NF1 patients and compared its predictive utility to that of the Elixhauser Comorbidity Index (ECI). Namely, we used the Nationwide Readmissions Database from 2016 to 2017 to select for those patients with a diagnosis of NF1 who underwent neurosurgical resection of an intracranial tumor. Patient frailty was queried through the use of the Johns Hopkins Adjusted Clinical Groups (JHACG) frailty-defining indicator. ECI scores were collected for these patients for measurement of comorbidities. Propensity score matching was performed for age, sex, ECI, insurance type, median income by ZIP code, and yielded 60 frail and 60 non-frail patients. Receiver operating characteristic (ROC) curves were created for relevant complications, including mortality, non-routine discharge, cost in top quartile, length of stay [LOS] in top quartile, and readmission, using comorbidity indices as predictor values. The area under the curve (AUC) of each ROC served as a proxy for model performance. Following matching of the groups, frail patients still had an increased average hospital cost ($85,441.67±$59,201.09) compared to non-frail patients ($49,321.77±$50,705.80)(p=0.010). Similar trends were also found for LOS between frail (23.1±14.2 days) and non-frail patients (10.7±10.5 days)(p=0.0020). For each complication of interest, ROC curves plotted showed frailty performing as well as ECI and the combination of Frailty+ECI (p &amp;gt;0.05). Frailty+ECI (AUC: 0.924)outperformed the model using only ECI (AUC: 0.842, p=0.027). These findings suggest that frailty is as efficacious as ECI in predicting complications including mortality, non-routine discharge, readmission, and high cost in patients who underwent resection of intracranial lesions associated with NF1.
ANGI-11. RAB27 IS REQUIRED FOR REGULATING INTACT VASCULATURE IN GLIOBLASTOMA
Authors: Lata Adnani, Brian Meehan, Janusz Rak
Journal: Neuro-Oncology (2022)

Abstract Rab27 is a GTPase involved in the biogenesis of extracellular vesicles (EVs) and cellular secretion pathway. Among two Rab27 isoforms (a and b) Rab27a has been identified in regulating angiogenesis during development and wound healing via VEGFR1. Here, we show that Rab27 plays a role in the development and stability of the brain vasculature including pathological angiogenesis in glioblastoma.. Thus, relative to wild-type C57bl/6 (WT) and double heterozygous Rab27a+/-;Rab27b+/- (dHET) mice, animals with Rab27a/b double knock-out (Rab27a/b-dKO) exhibit reduced microvascular density in brain cortices. Additionally, we also observed a reduction in permeability of Evans Blue in the Rab27 dKO cortices relative to controls. When neoangiogensis was induced following orthotopic inoculation of mouse glioma cells (GL261), a similar reduction and morphological anomalies were observed in the tumour vasculature relative to tumours established in control mice. Moreover, vascular permeability of tumours in Rab27a/b-dKO mice markedly exceeded that of similar tumours in wild type or heterozygous controls. Our results suggest Rab27a and Rab27b may play a critical role in ensuring stability of the vasculature under physiological conditions and in glioma.
SURG-24. QUANTITATIVE ANALYSIS OF TUMOR CELL DENSITY AND PROTOPORPHYRIN IX FLOURESCENCE IN GLIOMA PATIENTS USING PAIRED STIMULATED RAMAN HISTOLOGY AND TWO-PHOTON EXCITATION FLUORESCENCE MICROSCOPY
Authors: Mustafa Nasir-Moin, Lisa Irina Wadiura, Devin Juros, Misha Movahed-Ezazi, Matthew Lee, Hannah Weiss, Michael Müther, Daniel Alber, Sujay Ratna, Camila Fang, Eric Suero-Molina, Sönke Hellwig, Walter Stummer, Karl Rössler, Johannes Hainfellner, Georg Widhalm, Barbara Kiesel, David Reichert, Mario Mischkulnig, Rajan Jain, Jay Trautman, Steve Pastore, Donato Pacione, Dimitris Placantonakis, Eric Oermann, John Golfinos, Todd Hollon, Matija Snuderl, Christian Freudiger, Daniel Orringer
Journal: Neuro-Oncology (2022)

Abstract Fluorescence guidance is widely utilized to improve the precision of cancer surgery. 5-aminolevulinic acid, the most widely used fluorophore in glioma surgery, is thought to cause selective accumulation of fluorescent protoporphyrin IX (PpIX) in tumor cells by exploiting pathologic alterations in heme biosynthetic pathways. PpIX-induced fluorescence is highly specific for densely tumor-infiltrated tissue but less effective for visualizing the tumor periphery. To improve clinical detection of PpIX, we developed a microscope to perform paired stimulated Raman histology and two-photon excitation fluorescence microscopy (TPEF) and validated it in 175 fresh, unprocessed core tumor specimens from 75 high-grade glioma patients and three central nervous system lymphoma patients across three institutions. Surprisingly, intracellular PpIX accumulation was observed primarily in cells with histiocytic, rather than neoplastic morphology, and the number of cells concentrating PpIX within the cytoplasm was associated with the abundance of CD163 positive cells (p&amp;lt; 0.02). There was no correlation between the degree of tumor cellularity and the concentration of PpIX across all imaged specimens (R=-0.21). Our findings encourage reconsideration of the existing theory of 5-ALA-induced tumor cell fluorescence in gliomas and demonstrate how 5-ALA and TPEF imaging can provide a window into the immune microenvironment of human gliomas.
NCMP-24. RISK FACTORS OF SURGICAL SITE INFECTION IN GLIOMA SURGERY
Authors: Atsushi Kuwano, Masayuki Nitta, Taiichi Saito, Soko Ikuta, Shunsuke Tsuzuki, Shunichi Koriyama, Takakazu Kawamata, Yoshihiro Muragaki
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Surgical site infection(SSI) in neurosurgery can increase mortality and worsen functional outcome. There are few reports on risk factors for SSI in glioma surgery. In this study, we investigated the risk factors for SSI in glioma surgery at our institution. METHODS We included 1013 patients with gliomas who underwent craniotomy between November 2013 and March 2022 at our institution. SSI was defined as requiring surgical treatment. Various factors including age, gender, number of operations, prior radiology, prior chemotherapy, use of intraoperative MRI, operation time, tumor WHO grade were investigated. RESULTS Among 1013 craniotomies, 31 (3.06%) cases of SSI required surgical procedure. In univariate analysis, the most significant factors were multiple prior craniotomy (p = 0.0067) and prior radiation therapy ( p = 0.0286). Among these factors, multivariate analysis revealed the number of surgeries ( p = 0.0151) as a significant independent factor for infection.Discussion and CONCLUSION Patients with gliomas often requires multiple craniotomy due to tumor recurrence. Although there have been reported the reoperation is an independent risk factor for postoperative infection, the is the first time that a specific number of prior surgeries ( 2 or more) has been reported. Radiotherapy is said to cause skin damage at a threshold of 10 Gy or less. Since radiation therapy for gliomas is given a dose of 50 Gy or more and irradiated scalp causes radiation dermatitis, and patients who have undergone prior radiotherapy must be carefully monitored.
CSIG-27. MODULATION OF GPR133 (ADGRD1) SIGNALING BY ITS INTRACELLULAR INTERACTION PARTNER EXTENDED SYNAPTOTAGMIN 1 (ESYT1)
Authors: Gabriele Stephan, Hediye Erdjument-Bromage, Wenke Liu, Joshua Frenster, Tomas Neubert, David Fenyo, Dimitris Placantonakis
Journal: Neuro-Oncology (2022)

Abstract GPR133 (ADGRD1), a member of the adhesion GPCR (aGPCR) family, has been recently implicated in the pathogenesis of glioblastoma. Like other aGPCRs, GPR133 is characterized by a large N-terminus, which possesses a conserved GPCR autoproteolysis-inducing (GAIN) domain catalyzing cleavage at a GPCR proteolysis site (GPS), resulting in a C-terminal fragment (CTF) and an N-terminal fragment (NTF). We showed that dissociation of the cleaved NTF and CTF at the plasma membrane correlates with increased GPR133 signaling, which is mediated by coupling to Gs and increase in cytosolic cAMP. Since GPR133 is absent in normal brain cells and de novo expressed in GBM, it represents a potential target for GBM treatment. However, little is known about the receptor’s protein interactome and its effects on receptor function and signaling. To identify intracellular interactors of GPR133, we used a proximity biotinylation/mass spectrometry approach in HEK293T cells expressing the wild-type or a signaling-incompetent mutant GPR133. We identified Extended Synaptotagmin 1 (ESYT1), a protein responsible for Ca2+-dependent formation of endoplasmic reticulum-plasma membrane bridges, as the strongest interaction partner for both versions of the receptor. Co-immunoprecipitation confirmed robust binding of ESYT1 to GPR133. Knockdown/knockout of ESYT1 increased GPR133 signaling, while overexpression of ESYT1 had the opposite effect. This effect was not mediated by changes in GPR133 expression or plasma membrane trafficking. We are currently performing additional studies to elucidate the mechanism whereby ESYT1 modulates GPR133 signaling. Collectively, these data suggest that GPR133 signaling is modulated through a novel cytosolic, signaling-independent interaction with ESYT1.
CSIG-08. MASS CYTOMETRY IDENTIFIES LOCATION-SPECIFIC TUMOR POPULATION ASSOCIATED WITH CLINICAL PROGRESSION IN GLIOBLASTOMA
Authors: Alvaro Alvarado, Soniya Bastola, Sree Deepthi Muthukrishnan, Tyler Alban, Kaleab Tessema, Ichiro Nakano, Justin Lathia, Steven Goldman, Harley Kornblum
Journal: Neuro-Oncology (2022)

Abstract Recent advances in single cell expression technology have allowed us to appreciate the complexity in tumoral heterogeneity of solid tumors such as glioblastoma (GBM), which remains uniformly fatal despite aggressive therapies. Currently, there is no knowledge about cell identities and functional characteristics of the different tumoral populations. To this end, we created a 28-marker mass cytometry panel composed of signaling markers, including phospho-proteins, and lineage markers that have been associated with GBM or are considered putative cancer stem cell markers. We evaluated lines established from core and edge areas from the same patient and validated to be functionally different with RNA expression and in vivo experiments. We found clusters shared by cells from both regions as well as region-specific ones. In order to better characterize these, we used marker enrichment modeling (MEM) and generated machine-readable labels. These were compared to MEM labels generated after using the same signaling markers to cluster primary samples from newly diagnosed or recurrent patients. Similarly, MEM labels were obtained from patients in a clinical trial treated with capecitabine that had positive or negative responses. Clusters from edge cells were found in higher proportion in recurrent tumors and were correlated with negative responses to chemotherapy. Initial analyses have also been done correlating immune clusters with tumor clusters in the same samples. Edge clusters are characterized by a CD44+ SOX2+ Nestin+ population. Treatment of tumor cells with temozolomide and irradiation results in an increase of this population in vitro. We are currently conducting single cells analyses to characterize this population as well as in vivo studies to validate the tumor-immune interactions. Our studies exploit single cell cytometry to underscore pathways that are preferentially use by different populations and affect immune cells with the goal of establishing therapeutic efforts to extend patient survival.
PATH-01. EVALUATION OF RAMAN SPECTROSCOPY AS A DIAGNOSTIC TOOL IN NEUROPATHOLOGY FOR TUMOR CLASSIFICATION
Authors: Gilbert Georg Klamminger, Laurent Mombaerts, Finn Jelke, Redouane Slimani, Giulia Mirizzi, Karoline Klein, Andreas Husch, Frank Hertel, Michel Mittelbronn, Felix Kleine Borgmann
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Raman spectroscopy (RS) has shown its applicability in neurooncological diagnostics ranging from intraoperative tumor identification to peri- and postoperative tissue analyses. In the present study, we applied RS to track changes in the molecular vibrational status of a broad spectrum of formalin fixed paraffin-embedded (FFPE) intracranial neoplasms (primary brain tumors, meningiomas, brain metastases) and evaluated its potential as an additional method in the neuropathology toolbox, considering specific challenges when employing RS on FFPE tissue. Material and METHODS We examined 82 cases of intracranial neoplasms (679 individual measurements) by RS and applied a machine learning pipeline for recognition of spectral properties. The discrimination potential of the machine learning algorithms was evaluated using standard performance metrics such as AUROC and AUPR values, macro and weighted average of accuracy, precision, recall, and f1 scores. To address occurring misclassifications and further evaluate our models we searched for important Raman bands usable for tumor identification. RESULTS Using our trained machine learning model, we differentiated between different types of gliomas and determined the primary origin in case of a brain metastasis. We further spectroscopically diagnosed tumor types solely based on biopsy fragments of necrosis, something not possible by means of light microscopy. During the validation process we confirmed a high complexity within the spectroscopic data, possibly resulting not only from biological tissue which has undergone a rough chemical procedure but also from residual components of the fixation/paraffination process. CONCLUSIONS Our study demonstrates possibilities and limits of RS as a potential diagnostic tool in neuropathology, considering accompanying difficulties in the vibrational spectroscopic examination of FFPE tissue.
EXTH-06. PRE-INFUSION METABOLIC MODULATION OF CAR-T CELLS PROMOTES THE RESISTANCE TO THE SUPPRESSIVE EFFECTS OF HYPOXIA AND ENHANCES ANTI-TUMOR EFFECTS AGAINST INTRACEREBRAL GLIOMAS
Authors: Ryusuke Hatae, Keith Kyewalabye, Akane Yamamichi, Tiffany Chen, Pavlina Chuntova, Hideho Okada
Journal: Neuro-Oncology (2022)

Abstract Effective immunotherapy for glioma has not yet been established. We have found the energy metabolic status of immune cells within the tumor microenvironment is remarkably different between intracerebral and extracranial tumors. In mice bearing intracerebral SB28-EGFRvIII gliomas with intravenous infusion of EGFR vIII-targeting CAR-T cells, we found that mitochondrial markers in tumor-infiltrating T cells were down-regulated compared to those in splenic T cells. Therefore, we hypothesized that the treatment of CAR-T cells with a metabolic regulator that activates mitochondria before infusion would improve the therapeutic effect of CAR-T cells. Using a hypoxic incubator to mimic the tumor microenvironment of brain tumors, we screened drugs that would improve the metabolic state of CAR-T cells and sustain their anti-tumor effect. We have found that, although the mammalian target of rapamycin (mTOR) inhibitor rapamycin and AMP-activated protein kinase (AMPK) activator metformin are ineffective when administered as single drugs, the combined use of these drugs (met+rap) prolongs the anti-glioma effect of CAR-T cells under hypoxic conditions. A single intravenous infusion of CAR-T cells that were pre-treated with met+rap significantly prolonged the survival of mice bearing intracerebral SB28-EGRFvIII tumors compared with CAR-T cells without the pre-infusion treatment. Met+rap-treated CAR-T cells infiltrated the intracerebral tumor more effectively and maintained their functions better than the control CAR-T cells, suggesting that the met+rap treatment conferred CAR-T cells with abilities to traffick and function in the severe microenvironment of brain tumors. Importantly, because the CAR-T cells were pre-treated with the drugs during the in vitro expansion only but without drug administrations in vivo, this strategy would circumvent any toxicity associated with in vivo treatments with the same drugs. These data suggest that the treatment of CAR-T cells during the in vitro expansion with the two drugs may improve the efficacy of CAR-T cell therapy for brain tumors.
NCOG-36. DOSIMETRY AND COGNITIVE FUNCTION AFTER RADIATION THERAPY IN LOW GRADE GLIOMAS
Authors: Wafa Asha, Sami Koro, Wafa Asha, Wei Wei, Yanwen Chen, Eric Murray, Erin Murphy, John Suh, Samuel Chao, Lilyana Angelov, David Peereboom
Journal: Neuro-Oncology (2022)

Abstract PURPOSE We found that cognitive function remained stable following radiotherapy with concurrent and adjuvant temozolomide (RT+TMZ) in low-grade glioma (LGG) patients evaluated prospectively up to 2 years. This study evaluates the effects of radiotherapy dosimetry on neurocognitive function in a larger group of molecularly defined LGG patients treated with radiotherapy (RT). METHODS A total of 39 LGG patients were evaluated with comprehensive psychometric tests at baseline (prior to RT) and at various time intervals following RT. Patients served as their own controls by evaluating change in scores over time. Dosimetric parameters included mean and maximum dose to the pituitary, mean and maximum dose to the hypothalamus, mean dose to contralateral hippocampus, brain, cochlea, and PTV volume. Correlation between dosimetry and neurocognitive tests were assessed by Spearman correlation for the baseline correlation and Cox proportional hazard regression analysis for the survival analysis. RESULTS Patients were followed for a median of 60 months. Overall, patients showed group mean test scores similar to their initial performances following radiotherapy on all psychometric measures. There was a significant correlation between mean dose to cochlea (p=0.006), pituitary (p=0.035), mean PTV volume (0.019) and neurocognitive outcome.. CONCLUSION Cognitive function remained stable following radiotherapy in LGG patients evaluated prospectivelys. There was a significant correlation between specific dosimetric endpoints and neurocognitive outcomes over time. Further study needs to be done in a larger population to validate these findings.
EPID-06. IMPROVEMENTS IN SURVIVAL FOR GLIOBLASTOMA IN THE POST-STUPP PROTOCOL ERA
Authors: Corey Neff, Gordon Chavez, Christina Proescholdt, Carol Kruchko, Gino Cioffi, Kristin Waite, Jill Barnholtz-Sloan, Quinn Ostrom
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Introduction of the Stupp protocol for glioblastoma treatment in 2005 led to a significant increase in overall survival in glioblastoma. Prior analyses identified additional survival gains in glioblastoma since this time, though the source of these gains is unknown. In this analysis, we leveraged commercial claims and population-based datasets to better understand potential treatment factors associated with improved survival for glioblastoma. METHODS Provider-side commercial claims data were obtained from IQVIA for adults (18+) diagnosed with malignant brain tumor (ICD-9 codes: 191.0-191.9 or ICD-10 codes: C71.0-C71.9) from 2013-2021. Glioblastoma patients were identified as those who received biopsy/resection, radiation and temozolomide within 60 days of their brain tumor diagnosis. Treatment patterns were determined using ICD-9/ICD-10 procedure codes and HCPCS/CPT codes. Date of death was determined by a claim containing the CPT codes 99238 or 99239 or date of last claim followed by at least 30 days of no additional claims. Population-based survival data for microscopically-confirmed adult glioblastoma cases receiving radiation treatment from the National Program of Cancer Registries (NPCR) from 2004-2018 were used as a comparison group. Median survival was estimated using Kaplan-Meier regression, overall in IQVIA and by two-year periods in NPCR. RESULTS In the IQVIA cohort, 9,368 individuals (2.5%) were identified as glioblastoma based on treatment criteria. Median survival in the IQVIA cohort 16.6 months (15.2-17.0), and 12 months (95%CI:12-12) in NPCR. Median survival in NPCR increased from 11 months in 2004-2006, to 12 months in 2006-2009, and then 13 months in 2010-2018. Within the IQVIA cohort, 27% had ≥ 1 claim for Bevacizumab and 15% had ≥ 1 claim for tumor treating fields. CONCLUSIONS Survival in glioblastoma continues to improve over time, which may be due to developments of new therapeutic approaches. Assessment of population-level survival patterns is essential for understanding the impact of treatment advancements in the general population.
TMET-20. TERT ACTS VIA FOXO1 TO ALTER REDOX METABOLISM IN BRAIN TUMORS
Authors: Georgios Batsios, Celine Taglang, Meryssa Tran, Anne Marie Gillepspie, Pavithra Viswanath
Journal: Neuro-Oncology (2022)

Abstract Telomere maintenance is a fundamental hallmark of cancer. Most tumors maintain telomere length via reactivation of telomerase reverse transcriptase (TERT) expression. Identifying imaging biomarkers of TERT can enable non-invasive assessment of tumor proliferation and response to therapy. Deuterium magnetic resonance spectroscopy (DMRS) following administration of 2H-labeled substrates recently emerged as a novel, clinically translatable method of monitoring metabolic activity in vivo. The goal of this study was to delineate metabolic reprogramming associated with TERT expression and to leverage this information for non-invasive imaging of tumor burden and treatment response in gliomas. Our results indicate that TERT expression is associated with elevated levels of the redox metabolite NADH in glioblastomas and oligodendrogliomas. Mechanistically, TERT expression is associated with inhibitory phosphorylation and cytosolic sequestration of FOXO1. FOXO1, in turn, negatively regulates nicotinamide phosphoribosyl transferase (NAMPT), which is the rate-limiting enzyme in NAD+ biosynthesis. As a result, TERT upregulates NAMPT, resulting in elevated steady-state pools of NAD+ and NADH. Concomitantly, FOXO1 negatively regulates the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, which converts NAD+ to NADH. As a result, TERT upregulates the NADH/NAD+ ratio. Since elevated NADH and NADH/NAD+ ratio drive pyruvate conversion to lactate, we then examined whether DMRS-based imaging of [U-2H]-pyruvate metabolism reports on TERT expression in gliomas. Our results indicate that doxycycline-inducible TERT silencing significantly reduces lactate production from [U-2H]-pyruvate in tumor-bearing mice. Importantly, [U-2H]-pyruvate metabolism to lactate differentiates tumor from normal brain in vivo, including at clinical field strength (3T). Furthermore, [U-2H]-pyruvate reports on early response to treatment with TERT inhibitors or with radiochemotherapy in mice bearing orthotopic patient-derived gliomas at early timepoints before radiographic alterations can be visualized by magnetic resonance imaging. Collectively, our studies integrate a mechanistic understanding of TERT biology with innovative imaging that has the potential to improve assessment of tumor burden and treatment response for glioma patients.